Collaborating Investigators at Yale University School of Medicine have jointly developed a Program Project on the molecular basis of myelopoiesis. The research themes focus on the identification and characterization of genes that are critical in the normal pathway of differentiation from the pluripotent hematopoietic stem cell, through intermediate progenitor and precursor cell stages, to mature differentiated and functional neutrophils. These themes coalesce in efforts to improve our understanding of the molecular anatomy of gene expression in myelopoiesis and the specific pathways that regulate the differentiation, maturation and function of myeloid cells. This Program Project is organized into a team approach for the integrated pursuit of five research projects supported by one bioinformatics core and one administrative core. The individual projects address the characterization of the molecular correlates associated with the function of the homeobox gene HoxB4 that is preferentially expressed in primitive hematopoietic stem/progenitor cells; characterization of the role in hematopoiesis of the transcriptional co-factor SHARP and its isoforms; characterization of the molecular mechanisms by which the proto-oncogene Evi1 disrupts normal myelopoiesis; global genomic analysis of gene expression associated with myeloid specification; and study of the transcriptional regulation of neutrophil-specific gene expression. The bioinformatics core will provide state-of-the-art database management and analytical tools for the storing and interpretation of the genomic data generated by these projects. This Program Project application brings together investigators from four different departments of the institution, with a wide variety of basic research expertise to address a number of important questions in hematopoiesis.